DNA甲基转移酶1（DNMT1）抑制通过提高自噬水平来改善记忆样自然杀伤细胞的活性。
DNMT1 inhibition improves the activity of memory-like natural killer cells by enhancing the level of autophagy.
作者信息
Li Yixun, Guo Chong, Zhang Fujia, Cheng Shenju, Li Yanhong, Luo Shan, Zeng Yun, Zhao Yaling, Wu Kun
机构信息
Yunnan Key Laboratory of Laboratory Medicine, Yunnan Province Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China.
Department of Hematology, Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China.
出版信息
Mol Biol Rep. 2024 Dec 20;52(1):68. doi: 10.1007/s11033-024-10181-9.
BACKGROUND
Acute myeloid leukemia (AML) is a common hematological tumor, but it is difficult to treat. DNMT1 is a DNA methyltransferase whose main function is to maintain stable DNA methylation during the DNA replication process. DNMT1 also plays an important role in AML, but its function in cytokine-induced memory-like natural killer (CIML NK) cell activity remains unclear.
METHODS AND RESULTS
In this study, we isolated primary NK cells from the peripheral blood of healthy volunteers and AML patients and treated them with 10 ng/mL IL-12, 50 ng/mL IL-15 and 50 ng/mL IL-18 to promote their differentiation into CIML NK cells. The activity of CIML NK cells was evaluated by RT‒qPCR, western blotting, ELISAs, and flow cytometry. DNMT1 was highly expressed in NK cells from AML patients. Knocking down DNMT1 significantly increased the expression of CD25, CD137, CD107a, IFN-γ, and TNF-α and increased the activity of CIML NK cells. Mechanistically, knocking down DNMT1 promoted autophagy by activating the AMPK/mTOR signaling pathway, thereby enhancing the activity of CIML NK cells and alleviating the progression of AML.
CONCLUSIONS
Our study revealed that the downregulation of DNMT expression may be a new target for the treatment of AML.
背景
急性髓系白血病（AML）是一种常见的血液肿瘤，但治疗困难。DNMT1是一种DNA甲基转移酶，其主要功能是在DNA复制过程中维持稳定的DNA甲基化。DNMT1在AML中也起重要作用，但其在细胞因子诱导的记忆样自然杀伤（CIML NK）细胞活性中的功能仍不清楚。
方法和结果
在本研究中，我们从健康志愿者和AML患者的外周血中分离出原代NK细胞，并用10 ng/mL白细胞介素-12、50 ng/mL白细胞介素-15和50 ng/mL白细胞介素-18处理，以促进其分化为CIML NK细胞。通过RT-qPCR、蛋白质免疫印迹法、酶联免疫吸附测定和流式细胞术评估CIML NK细胞的活性。DNMT1在AML患者的NK细胞中高表达。敲低DNMT1可显著增加CD25、CD137、CD107a、干扰素-γ和肿瘤坏死因子-α的表达，并增加CIML NK细胞的活性。机制上，敲低DNMT1通过激活AMPK/mTOR信号通路促进自噬，从而增强CIML NK细胞的活性并缓解AML的进展。
结论
我们的研究表明，DNMT表达下调可能是治疗AML的新靶点。
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